The primary objective of this work is to further elucidate the pathophysiology of acclerated atherosclerosis observed in diabetes mellitus. Increased understanding may lead to rational and effective prevention of premature vascular disease, the major cause of morbidity and mortality in diabetic patients. The studies described herein will test the hypothesis that very low density lipoproteins and postprandial d less than 1.019 lipoproteins from diabetics are functionally abnormal with respect to interactions with cellular lipoprotein receptors and macrophage secretory products (e.g. lipoprotein lipase, apoprotein E). The cell types that participate in the formation of the atherosclerotic plaque lesion, arterial smooth muscle and macrophage cells will be isolated and grown in culture. Because we have previously shown that factors secreteted by macrophages may modulate the progression of the vessel wall plaque, conditioned medium experiments will be performed to further evaluate the influence of macrophage secretory products on triglyceride-rich lipoprotein metabolism by mesenchymal cells. Lipoproteins isolated from finite numbers of well characterized diabetics and controls will be studied with these cells in culture. The effects of lipoproteins on cellular lipid metabolism will be evaluated by assaying 14C-oleic acid incorporation into cholesterol ester and triglyceride and by direct measurement of cellular triglyceride and cholesterol ester mass. Lipoprotein interaction with specific cell surface receptors will be studied using iodinated lipoproteins in binding and degradation assays as described in our previous publications. Saturation curves will be constructed and competition studies will be performed to further characterize the nature of lipoprotein-receptor interactions. All subjects will be characterized with respect to age, body mass index, medications and lipoprotein profile. Diabetics will be further characterized with respect to history of ketosis, degree of control (fasting blood sugar and HgbAlc), treatment regimen (diet, oral agents, insulin), duration of diabetes, and the presence of clinically apparent vascular disease. The use of well characterized groups of normo- and hypertriglyceridemic type I and type II diabetics, and controls, matched for age, weight and lipoprotein profile should allow the correlation of our results to the potentially independent factors of type of diabetes, degree of hypertriglyceridemia, mode of treatment and degree of control. Subfractionation and analysis of VLDL particles will also be performed for the above patient groups.